The Spatial Redox–Metalloptosis Axis in Liver Disease: A Hypothesis on Regional Susceptibility to Ferroptosis and Cuproptosis

The pathogenesis and progression of liver diseases are characterized by marked zonal heterogeneity, yet conventional research paradigms have long overlooked this intrinsic spatial logic. Ferroptosis and cuproptosis have been widely implicated in liver disease; however, their precise intralobular distribution and zonal susceptibility patterns remain poorly defined. We present a narrative synthesis of the literature on the spatial zonation of hepatic metabolism, redox homeostasis, and metal handling, and assess their potential roles as determinants of region-specific cell death vulnerability. We propose the novel “spatial redox–metalloptosis axis” hypothesis. The pericentral zone (Zone 3), characterized by hypoxia, high cytochrome P450 activity, and a redox environment that may favor lipid peroxidation under specific pathological conditions, is hypothesized to form a ferroptosis-susceptible niche under metabolic stress. Conversely, the periportal zone (Zone 1), characterized by active copper handling and oxidative phosphorylation-dependent metabolism, is hypothesized to be preferentially vulnerable to cuproptosis (proposed hypothesis; direct zone-resolved evidence of cuproptosis execution in Zone 1 is currently absent). Ceruloplasmin is proposed as a candidate molecular link between copper and iron metabolism. We further identify shared molecular hubs and a hypothesized spatial redox–metalloptosis axis linking these two regulated cell death modalities, while direct biological crosstalk remains to be demonstrated. We also highlight critical technological, mechanistic, and translational gaps. This review aims to shift liver disease research from viewing the liver as a homogeneous organ to a functionally compartmentalized zoned ecosystem, providing a testable theoretical framework for deciphering region-specific liver injury and developing spatially informed therapeutic strategies.